The schizophrenia spectrum disorders include schizophrenia (SZ), schizotypal personality disorder (SPD), and schizoaffective disorder (SD). Schizophrenia (SZ) is considered a clinical syndrome, and is probably a constellation of several pathologies. Substantial heterogeneity is seen between cases, which is thought to reflect multiple overlapping etiologic factors, including both genetic and environmental contributions. SD is characterized by the presence of affective (depressive or manic) symptoms and schizophrenic symptoms within the same, uninterrupted episode of illness. SPD is characterized by a pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior, beginning by early adulthood and present in a variety of contexts.
Bipolar Disorder (BD), which is also known as manic-depression or manic-depressive disorder, is characterized by mood that alternates between two emotional extremes, or poles: the sadness of depression and the euphoria of mania. BD includes the following clinical disorders: Bipolar I disorder, Bipolar II disorder, Bipolar mania, and Bipolar depression.
Both schizophrenia and bipolar disorder can be classified as psychotic disorders. Indeed, BD and SZ are clinical classifications rather than actual diseases. The two diagnoses share many common features, with BD subjects often suffering in particular from extensive delusions similar to those seen in SZ. Similarly, SZ patients often have substantial affective symptoms such as mania and depression. Indeed, BD and SZ can be considered two ends of a continuum of mental illness, with BD diagnosis focused more on affective symptoms (e.g., mania and depression) and SZ more focus on positive symptoms (e.g., hallucinations). The diagnosis given to a patient often depends on the symptoms presented at time of diagnosis, which may or may not reflect the full extent of that patient's disease.
Differential diagnosis represents a tremendous area of unmet medical need. One area in particular in which this unmet need is evident is choice of medication. Two prime examples are the use of SSRI antidepressants to treat affective symptoms in SZ (which would be counter-indicated in patients with a high BD vs SZ index) and antipsychotic treatment for some BD subjects. Other examples could include the addition of cognitive enhancers for subjects diagnosed with BD but scoring high for diagnosis of SZ vs BD.
Various genes and chromosomes have been implicated in etiology of SZ and BD. Many studies have suggested the presence of one or more important genes relating to SZ and BD on most or all of the autosomes (Williams et al., Hum. Mol. Genet. 8:1729-1739 (1999); Middleton et al., Am. J. Hum. Genet. 74:886-897 (2004); Matsuoka et al., Synapse 62:1-7 (2008); Fallin et al., Am. J. Hum. Genet. 77:918-936 (2005); Sklar et al., Mol. Psychiatry 13:558-569 (2008); Sun et al., Am. J. Med. Genet. B Neuropsychiatr. Genet. (2008); Badner et al., Mol. Psychiatry 7:405-411 (2002); Bennett et al., Mol. Psychiatry 7:189-200 (2002); Cooper-Casey et al., Mol. Psychiatry 10:651-656 (2005); Devlin et al., Mol. Psychiatry 7:689-694 (2002); Fallin et al., Am. J. Hum. Genet. 73:601-611 (2003); Ginns et al., Proc. Natl. Acad. Sci. U.S.A 95:15531-15536 (1998); Jablensky, Mol. Psychiatry (2006); Kirov et al., J. Clin. Invest. 115:1440-1448 (2005); Norton et al., Curr. Opin. Psychiatry 19:158-164 (2006); Owen et al., Mol. Psychiatry 9:14-27 (2004)) However, none of these prior studies have used high resolution genetic association methods to systematically compare genes involved in psychosis, SZ and BD. Neither have any of these studies demonstrated that genetic polymorphisms in the genes defined herein are important, in particular in the genetic etiology of psychosis, or BD.
Due to the severity of these disorders, especially the negative impact of a psychotic episode on a patient, and the diminishing recovery after each psychotic episode, there is a need to more conclusively identify individuals who have or are at risk of developing bipolar disorder (BD) or schizophrenia spectrum disorders in order to, for example, confirm clinical diagnoses, allow for prophylactic therapies, determine optimal therapies, and provide genetic counseling for prospective parents with a personal or family history of the disorder.